Quinazolone derivatives



United States Patent ice 3,304,304 QUINAZOLONE DERIVATIVES Volkert Claassen and Gerardus Henricns Maria Mos, both of Van Houtenlaan, Weesp, Netherlands, assignors to North American Philips Company, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Mar. 18, 1965, Ser. No. 440,952 Claims priority, application Netherlands, Mar. 24, 1964,

7 Claims. (Cl. 260-251) The invention relates to new compounds of the Formula I and salts thereof,

in which formula X is a halogen atom, preferably a chlorine atom or the --CF;,--- group and R is an alkyl group having l-3 carbon atoms. Of these compounds an interesting pharmacological activity was found, as a result of which these compounds according to the invention may be used as active constituents in drugs. In particular, a strong central depressive activity was found. The sedative activity of the compounds according to the invention was found inter alia in experiments in which the potentiating effect of the substances on the depressive effect of hexobarbital was determined in mice. The substances to be investigated were administered intraperitoneally 30 minutes or orally 60 minutes before a dose of hexobarbital which was just not narcotiv (30 mg./kg.) and-which was administered intravenously. The ED value was calculated from the results of 4 dosage groups. In Table I these ED values of substances according to the invention are stated, while in this table also, for comparison, the ED value for a few known chemically closely related 4-quinazolone de- 3,304,304 Patented Feb. 14, 1967 In addition it'was found that the compounds according to the invention have a particularly prolonged activity. On oral administration, for example, of mg./kg. of 8-chloro-3-ethyl-4-quinazolone it was found that as long as 4 hours after the administration 30 mg. of hexobarbital were sufficient to cause half of the experimental animals to be narcotized.

In addition it was found that the compounds according to the invention have a strong anticonvulsive activity as could be established with respect to convulsions which were produced by a supermaximum dosage of cardiazol. In'this case the effect in the mouse was determined of a dosage of 50 mg./ kg. of cardiazol 60 minutes after oral administration of the compound to be investigated. In this case it was found that after oral administration of 54 mg./ kg. of 8-chloro-3-ethyl-4-quin|azolone convulsions did not appear in half of the experimental animals. The acute toxicity LD of the compounds was determined in the usual manner in mice and, on oral administration, always turned .out to be above 460 mg./kg. at 48 hours after administration. The LD of the 3-ethyl-8-chloro compound, for example, is 880 rug/kg.

Both the free bases and the salts of the compounds according to the invention can be used for the preparation of pharmaceutical compositions. As such non-toxic acid addition salts may be mentioned, for example, the salts of the compounds according to the invention with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, sulfamic acid, tartaric acid, acetic acid and citric acid.

The pharmacologically active substances can be processed in any known manner to pharmaceutical compositions, for example, tablets, coated tablets, suppositories or injection liquids, by mixing them with or dissolving them in solid or liquid carrier materials commonly used in pharmacy, for example, starch, talcum powder, lactose, gelatine, Na-carboxymethyl cellulose, magnesium stearate and/ or mixtures thereof as solid carrier materials and, for example, water rendered isotonic with blood by means of salt, or Water mixed with, for example, glycerine as liquid carrier materials.

The compounds according to the invention can be prepared according to methods which are known per se for the preparation of this type of compounds and according to methods analogous thereto.

A suitable method is, for example, that in which an aminoalkyl group is introduced in a compound with a two-ring-system.

The compounds according to the invention can be prepared according to this method by causing a compound of the Formula III,

in which X has the same meaning as X in Formula I or represents an N0 group, Y is an oxygen atom or an NR; group and R is a hydrogen atom or a metal atom, to react with a compound of the formula RZ, where R has the same meaning as in Formula I and Z represents a halogen atom or an R50 group in case Y represents an NR group, and is an NH group in case Y is an oxygen atom or an NH group, and reducing the N group possibly present in the reaction product and converting the diazonium compound obtained by diazotation of the amino group into a halogen compound.

, The compounds according to the invention can be prepared in particular with a very good yield by causing a compound of the Formula IV,

in which X has the above meaning, to react, preferably in an inert solvent, for example, an alcohol or dimethylformamide, and in the presence of a base, for example, potassium hydroxide, pyridine, collidine, or a tertiary :amine, with an alkyl halongenide, preferably a bromide or chloride.

Alternatively, an alkali metal derivative or an alkaline earth metal derivative of a compound of Formula IV, in particular the sodium derivative or potassium derivative, preferably suspended or dissolved in an inert solvent, for example, benzene or toluene, may be caused to react at elevated temperature with an alkyl halogenide or an alkyl sulphate to prepare the compounds according to the invention. The preparation may also be carried out by causing a compound of the Formula 1V to react at elevated temperature in an autoclave while splitting off ammonia with an alkyl amine having 1-3 carbon atoms.

. By causing a compound of the Formula V in which X has the above meaning, preferably dissolved in an inert solvent, for example, toluene, xylene, cyclohexane or ligroin, to react at elevated temperature with an alkyl amine having '1-3 carbon atoms, the compounds according to the invention may be prepared also. This reaction is in particular successfully carried out in the presence of a catalytic quantity of this strong base. As such are to be considered inter alia alkali hydroxides, for example, potassium hydroxide or sodium hydroxide.

The starting substance of the Formula V may be obtained, for example, by heating N-formyl anthranilic acid substituted by X in 3-position, where X has the above meaning, with an acid anhydride, for example, acetic acid anhydride.

The substance of Formula IV may be prepared, for example, from the anthranilic acid substituted by a group X in 3-position, where X has the above meaning, by heating it a few hours, with formamide.

Another example of a known method which may be used for the preparation of the compounds according to the invention consists of a reaction in which these -corn pounds are formed immediately by ring closure of an anthranilic acid'deriv-ative.

According to this method, a compound of the Formula VI NHR" Where X has the same meaning as in Formula III, R' means an OH-group or an NHR- group, wherein R is an alkyl group having l-3 carbon atoms and R" is an H- atom or a formyl group, may be ring-closed immediately in case R is an -NHR-group and R is a .formyl group, or may be caused to react with an N-alkyl-formamide, in which the alkyl group contains l-3 carbon atoms, if R represents an OH-group and R" an H-atom, or with orthoformic acid ethyl ester, if R is an NHR-group and R" is an H-atom, or with an alkyl amine having 1-3 carbon atoms, preferably in the presence of a dehydrating agent, if R means an OH-group and R" a formyl group and reducing the NO -group possibly present in the reaction product and converting the diazonium compound obtained by diazotation of the amino group into a halogen compound.

For example, the compounds according to the invention may be obtained in a good yield by causing a compound of the Formula VI, where R represents an OH- group and R" an H-atom, whether or not dissolved in an inert solvent, for example, methylcellosolve, xylene or glycol, to react with the N-alkylformamide for a fe hours at high temperature.

The ring closure of the compound of Formula VI, in which R is an NHR-group and R" is a formyl group, may be carried out, for example, by adding to the substance a mixture of acetic acid anhydride and a small quantity of phosphonic acid and causing the mixture to react by heating it for some time. t

In another embodiment of this reaction, the mixture of the compound of Formula VI, where R is an NHR-group and R" an H-atom, is refluxed for a'few hours with an excess, for example, the 5-fold volume, of orthoformic acid ethyl ester.

Another example of a variation of this ring closure reaction is that in which a compound of the Formula VI, where R" is a formyl group and R an NHR-group, is caused to react under the influence of heat or a base, for example, sodium carbonate, sodium hydroxide solution or a tertiary amine. Start may also bemade for a compound of the formula VI where R is an OH-group and R" a formyl group, and this substance may be caused to react, in a hot inert liquid, for example, toluene or xylene, in the presence of a dehydrating agent, for example, PCl- P001 PCl PBr with an alkyl amine having 1-3 carbon atoms.

In order that the invention may readily be carried into effect, it will now be described more fully, by way of example, with reference to the ensuing specific examples.

EXAMPLES (1) 8-chl0r0-3-methyl-4-quinaz0l0ne.-3.05 g. of 8- chloro-4-quinazolone, 1.32 g. of potassium hydroxide and 2 ml. of methyliodide were'added to 40 ml. of methanol. The whole was shaken and stored in the dark at room temperature for 5 hours while shaking now and again. At the end of the reaction, the mixture reacted neutral with respect to litmus. The solvent and the excess of methyl iodide were removed at reduced pressure and the solid residue was stirred with 30 ml. of water and 10 ml. of 2 N sodium hydroxide solution. Then the liquid was sucked off and the'precipitate was washed alkali-free with water. Yield after drying over CaCl 2.92 g. Melting-point: 158-9 C.; after recrystallization from 50% methanol: 159-160 C.

(2) 8-chl0r0-3-ethyl-4-quinazolone.4.3 g. of 8- chloro-4-quinazolone, 1.5 g. of, 85% potassium hy droxide and 4 ml. of ethyliodide were boiled in 40 ml. of alcohol. After 1 hour a clear solution was obtained which reacted neutral with respect to litmus. The solution was cooled and the solvent and the excess of ethyl iodide were removed at reduced pressure.

The residue was thoroughly stirred with 40 ml. of water in which 1.5 g. of potassium hydroxide had been dissolved, after which the wash liquid was sucked off. The precipitate was dried in air. Yield: 3.50 g. Melting point 120 C.; recrystallized from acetone-water (3:10):

(3) 8-chl0ro-3-n-pr0pyl-4-quinazolone.3 g. of 8- chloro-4-quinazolone, 940 mg. of 85% potassium hydroxide and 2.05 g. of n-propyl bromide were boiled in 50 ml. of ethanol until neutral reaction to litmus. At the end of the reaction the mixture was evaporated at reduced pressure and the residue was stirred with 25 ml. of water and 8 ml. of 2 N sodium hydroxide solution. Then the wash liquid was sucked off. The precipitate was washed with water and dried in air. Yield 2.06 g. Melting-point 107l09.5 C.; after recrystallization from water: 110-112 C.

(4) 8-chlore-3-is0pr0pyl-4-quinaz0l0ne.3 g. of 8- chloro-4-quinazolone, 940 mg. of 85% potassium hydroxide and 3.2 ml. of isopropyl bromide were heated on the steam bath in 50 ml. of dimethyl formamide until the mixture reacted neutral on litmus. Then it was cooled, the potassium bromide formed was filtered off and the filtrate was evaporated to dryness at produced pressure. The residue was taken up in 50 ml. of chloroform and washed with a mixture of 20 ml. of water and 6 ml. of 2 N sodium hydroxide solution. After washing again with water, the chloroform layer was dried and evaporated at reduced pressure. The residue was dis solved in ether, after which 5 ml. of 3.8 N alcoholic hydrochloric acid were added. The resulting precipitate was filtered off, washed with ether and dried. Yield 2.15 g. Melting-point 172175 (decomposition); after recrystallization from alcohol ether 174.5-176 (decomposition).

The base was released from the hydrochloric acid salt by stirring the substance in 1 N sodium hydroxide. The solution was extracted with chloroform, after which the extract was dried and the chloroform removed at reduced pressure. The crystalline residue, recrystallized from hot water, melted at Ill-112 C.

(5) 8-chloro-3-n-propyl-4-quinaz0Z0ne.A solution of 3 ml. of phosphorus trichloride in 12 ml. of dried toluene was dropwise added with stirring to 8.27 g. of 3 -chloro- N-formyl-anthranilic acid, 7 ml. of n-propylamine dried on sodium sulphate and 60 ml. of toluene. After a gellike mass had formed under heat development, the mixture was boiled for two hours. The liquid, in which a yellow solid had formed, was rendered alkaline with respect to litmus after cooling with a 15% soda solution. The toluene was then removed by stern distillation and the aqueous residue extracted with chloroform. After drying on sodium sulphate the chloroform was removed from this extract under reduced pressure. The residue was recrystallized from water. Yield: 3.2 g. Melting point 110-112 C.

(6) 8-bromo-3-ethyl-4-quinaz0lone.3.'8 g. of 8-nitro- 4-quinazolone, 1.35 g. of 85% potassium hydroxide and 3 ml. of ethyl iodide were added to 75 ml. of alcohol. After the mixture had boiled for two hours, the solvent was distilled off under reduced pressure. The residue was stirred with 20 ml. of water and 10 ml. of 2 N potassium hydroxide. After filtration, the precipitate was washed with water and dried. Melting point 143- 144 C.

3.3 g. of the resulting 8-nitro-3-ethyl-4-quinazolone were dissolved in 110 ml. of methylcellosolve and reduced by introducing hydrogen under 3 atmospheres in the presence of 1.5 g. of 10% palladium/carbon catalyst.

After the required quantity of hydrogen had been taken up, the catalyst was filtered off and the solution evaporated to a small value. To this solution were added 50 ml. of ether, after which the amino compound crystallized out. Melting point 126.5l28 C.

950 g. of 8-amino-3-ethyl-4-quinazolone were dissolved in 1.5 ml. of 48% hydrobromic acid, after which the solution was cooled to 0 C. and 375 ml. of sodium nitrate dissolved in Water were added. After the solution of the diazoniurn compound was poured into a boiling solution of 1.6 g. of potassium bromide, 0.55 g. of cupro-bromide and 0.32 ml. of 48% hydrobromic acid in 3 ml. of water, an oil separated, which, after boiling for some time, was separated from the water layer. The oil was dissolved in chloroform after having been washed with 10 ml. of water. The resulting solution was washed with water and dried on sodium sulphate, after which the chloroform was removed under reduced pressure. The residue which was dissolved in 5 ml. of acetone, was discolored with norit. The norit was filtered off and 20 ml. of hot water were added to the filtrate. On cooling 8-bromo-3-ethyl-4-quinazolone crystallized out. Yield: 270 mg. Melting point 1'21122 C.

(7) 3-ethyl-8-triflu0romethyl-4-quinaz0l0ne.-4 ml. of a 30% hydrogen peroxide solution in water were added dropwise in approximately 20 minutes to a stirred solution of 2 g. of 7-trifluoromethyl-isatine in 25 ml. of a 5% sodium hydroxide solution. The temperature of the reaction mixture was kept below 50 C. After completion of the reaction, stirring was continued for another 30 minutes. The solution was then treated with norit and acidified with acetic acid till pH 5. The resulting precipitate was sucked off and washed with water. Yield: 1.38 g. Melting point 156157 C.

5 .65 g. of 3-trifluoromethyl-anthranilic acid and 5.5 ml. of formamide were thoroughly mixed, heated at 140 C. for 45 minutes and then kept at 180 C. for 2 hours. The reaction mixture partly solidified. After cooling, the solid residue was stirred in 25 ml. of water and then sucked off. Yield 4.9 g. Melting point 225227 C.

4.8 g. of 8-trifiuoromethyl-4-quinazolone and 1.3 g. of potassium hydroxide were added to 75 ml. of alcohol. To this mixture were added 8 ml. of methyl iodide. The whole was refluxed for 2 hours. Norit was added to the reaction mixture. The liquid was filtered and the pale-yellow filtrate evaporated to dryness in vacuo. The residue was taken up in a mixture of ml. of chloroform, 10 ml. of water and 5 ml. of 2 N-potassium hydroxide. After thoroughly shaking, the chloroform extract was separated, dried on sodium sulphate and evaporated to dryness in vacuo. The residue was stirred in ether. Yield: 2.17 g. Melting point 15215-154 C. After recrystallization from alcohol the melting point was 156-157 C.

(8) Injection liquid-70 l. of distilled water and 2.5 kg. of glycerine were brought into a mixing vessel. Then a solution of 0.5 kg. of the salt obtained according to Example 4 in 40 l. of distilled water was added, while stirring, after which the contents of the mixing vessel were replenished to 100 l. with distilled water. The injection liquid obtained after thoroughly stirring was further dispensed in the normal manner in ampoules which each contained 2 ml. of the injection liquid.

(9) Tablets which may contain the compounds according to the invention as the active substance may consist, for example, of 50 mg. of the active substance, 112 mg. of lactose, 50 mg. of potato starch, 10 mg. of talcum, 3 mg. of magnesium stearate.

What is claimed is:

1. 8-chloro-3-methyl-4-quinazolone.

2. 8-chloro-3-ethyl-4-quinazolone.

3. 8-chloro-3-n-propyl-4-quinazolone.

4. 8-chloro-3-i-propyl-4-quinazolone.

5. 8-bromo-3-ethy1-4-quinazo1one. 6. 8-trifluoromethyl-3-ethyl-4-quinazo1one.

7. A quinazolone derivative selected from the group consisting of the quinazolones of the formula:

wherein X is a member of the group consisting of halogen and the CF group, and R is alkyl of 1-3 carbonatoms and the non-toxic acid addition salts thereof.

References Cited by the Examiner NICHOLAS S. RIZZO, Primary Examiner. HENRY 1. JILES, Examiner. 

7. A QUINAZOLONE DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF THE QUINAZOLONES OF THE FORMULA: 